New Genetic Mechanism Identified in Autism Development

Recent research conducted by scientists at The Hospital for Sick Children (SickKids) and the University of Las Vegas, Nevada (UNLV) has uncovered a novel genetic link associated with autism spectrum disorder (ASD) and a rare inherited condition known as myotonic dystrophy type 1 (DM1). Published in Nature Neuroscience, the study reveals that a specific genetic variation involving tandem repeat expansions (TREs) in the DMPK gene impacts brain development and may contribute to ASD-related behaviors.

While autism has traditionally been linked to loss of gene function, this research suggests an alternative mechanism involving disruptions in gene splicing — a critical process for proper gene expression. The TREs cause abnormal RNA molecules, termed "toxic RNA," which sequester proteins essential for gene regulation during brain maturation. This sequestration leads to an imbalance in proteins, resulting in mis-splicing of multiple genes crucial for neural function.

Notably, DM1 causes progressive muscle weakness and is characterized by TREs in the DMPK gene. The study found that individuals with DM1 are 14 times more likely to develop ASD compared to the general population. The genetic variations disturb gene splicing processes, which may explain the social and behavioral challenges seen in some individuals with ASD, especially those with DM1.

The research team, including collaborators from various institutions, demonstrated that expanded TREs in the DMPK gene alter RNA molecules that interfere with proteins involved in brain development. This mis-splicing affects multiple genes associated with ASD, paving the way for potential targeted therapies. Efforts are underway to explore molecules that could reverse TRE expansions and normalize protein function, inspired by earlier research into similar mechanisms in Huntington’s disease.

Dr. Ryan Yuen from SickKids emphasizes that these findings offer a new perspective on the genetic roots of autism, highlighting the importance of understanding dysregulated RNA processes. Future studies aim to investigate the broader implications of gene splicing errors in ASD and develop precision medicine approaches to mitigate these molecular disruptions.